Frailty and transplant-free survival of patients with liver cirrhosis: A meta-analysis

Background Frailty is a common condition among patients with liver cirrhosis. Nonetheless, its role in predicting liver transplant-free survival (TFS) remains unclear. Aim This systematic review and meta-analysis were conducted to elucidate the relationship between frailty and TFS in patients with cirrhosis. Methods Cohort studies addressing the objective of this meta-analysis were extracted from PubMed, Embase, and Web of Science databases. Between-study heterogeneity was assessed with the Cochrane Q test, and the I^2 statistic was estimated. Random-effect models, considering potential heterogeneity, were employed to combine the results. Results The meta-analysis encompassed 17 cohort studies involving 6273 patients with cirrhosis, of whom 1983 (31.6%) were classified as frail at baseline. The follow-up periods in the included studies ranged from 3 to 29 months, with an average duration of 11.5 months. The analysis revealed that frailty was significantly associated with a poor TFS (risk ratio [RR]: 2.07, 95% confidence interval: 1.72 to 2.50, p<0.001; I2 = 51%). Sensitivity analyses that sequentially omitted one dataset consistently supported these findings (RR: 1.95 to 2.17, p<0.05 in all cases). Subgroup analyses based on variables such as study design, mean age of patients, baseline Model for End-Stage Liver Disease score, tool used for frailty evaluation, follow-up duration, and study quality score also yielded congruent results. Conclusions The evidence suggests that frailty may be an independent risk factor for poor TFS in patients with liver cirrhosis, thus emphasizing the importance of early identification and management of frailty in this population.


Introduction
Liver cirrhosis is a prevalent manifestation of advanced liver diseases, encompassing chronic viral hepatitis, alcoholic liver disease, and non-alcoholic fatty liver disease [1,2].This condition detrimentally affects various aspects of health-related quality of life, including mental wellbeing and physical factors, while also diminishing the functional capacity of affected individuals [3,4].On a global scale, cirrhosis is responsible for more than 2 million fatalities annually [5,6].Currently, no evidence-based pharmacological interventions are capable of reversing the fibrosis that leads to cirrhosis [7].Consequently, liver transplantation remains the sole curative alternative for individuals in the end-stage of cirrhosis [8].Given the multifactorial and intricate pathogenesis of liver cirrhosis, it is reasonable to explore innovative approaches for risk stratification in cirrhosis patients.In the clinical realm, frailty has emerged as a potential factor within the framework of comprehensive geriatric assessment, denoting a state of cumulative deterioration across various physiological systems and heightened susceptibility to unfavorable outcomes [9,10].Notably, frailty has been demonstrated as a substantial prognosticator of overall mortality in elderly individuals [11].Subsequent analysis indicates that in addition to the older community population, frailty may also serve as a risk factor for poor prognosis in patients with diverse chronic diseases, including cardiovascular diseases [12] and cancer [13].Earlier studies have demonstrated the prevalence of frailty in patients with liver cirrhosis, ranging from 17% to 43% [14].However, it remains uncertain whether frailty can accurately predict the clinical outcome of patients with cirrhosis [15].Consequently, we conducted a systematic review and meta-analysis to examine the potential correlation between frailty and liver transplant-free survival (TFS) in patients with cirrhosis.

Materials and methods
Throughout the process of planning, conducting, and reporting the study, the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement [16] and Cochrane Handbook [17] were followed.

Search of databases
We searched electronic databases, including PubMed, Embase, and Web of Science, starting inception and ending July 22, 2023, for studies published by that date.The search was performed with the terms including (1) "frailty" OR "frail"; and (2) "cirrhosis" OR "cirrhotic" OR "liver fibrosis" OR "hepatic fibrosis."Only human studies published in English as full-length articles in peer-reviewed journals were considered.As part of our manual screening process, references from relevant original and review articles were screened for possible relevant studies.

Inclusion and exclusion criteria of studies
Inclusion criteria were developed per the PICOS recommendations and according to the aim of the meta-analysis.P (patients): Adult patients (18 years or older) with a confirmed diagnosis of liver cirrhosis.I (exposure): Patients with frailty at baseline.Methods for evaluating frailty were consistent with those of the original studies.
C (control): Patients without frailty at baseline.O (outcomes): The incidence of liver transplant-free survival (TFS) compared between cirrhotic patients with and without frailty at baseline, with a follow-up duration of at least three months.The TFS was defined as being alive without having undergone a liver transplant, and it was selected as the outcome of the meta-analysis because this is an essential hard clinical outcome for patients with liver cirrhosis, which have been frequently used in previous high-quality clinical trials of liver cirrhosis [18][19][20].
S (study design): Cohort studies, which included prospective and retrospective cohort studies.
Reviews, editorials, studies that included other liver diseases rather than cirrhosis, and studies that did not evaluate frailty or did not report the outcome of interest were excluded.Studies with a follow-up duration of <3 months were also excluded because we did not want to investigate the acute influence of frailty on the clinical outcome of patients with cirrhosis.In cases of overlap in patient populations, the study with the largest sample size was included in the meta-analysis.

Data extraction and quality evaluation
The two authors carried out literature searches, data collection, and study quality assessments independently.In case of discrepancies, a third author was contacted for a discussion to reach a consensus.Among the studies included in the analysis, we collected information regarding study information, design characteristics, diagnosis of the patients, demographic factors, severity of the disease (model for end-stage liver disease [MELD] score), evaluating scale for frailty, number of patients with frailty in each study, follow-up durations, and variables adjusted when the association between frailty and TFS of patients with cirrhosis were evaluated.In terms of quality, the study was scored using the Newcastle-Ottawa Scale [21] based on the criteria for participant selection, the comparability of the groups, and the validity of the outcomes.Nine stars were on the scale, with a larger number representing a better study.

Statistics
Risk ratios (RRs) corresponding to a 95% confidence interval (CI) were used as the variables to indicate the association between frailty and liver transplant-free mortality of patients with cirrhosis.An RR>1 indicates a worse TFS in patients with frailty at baseline.A logarithmical transformation was performed on the RR and its corresponding stand error (SE) from each study to stabilize and normalize its variance [22].In order to estimate between-study heterogeneity, the Cochrane Q test and the I 2 statistic [23] were used.An I 2 >50% indicates that there is significant heterogeneity between studies.A random-effects model was applied to pool the results because this model has been considered to incorporate the influence of potential heterogeneity [17].Sensitivity analyses excluded one dataset at a time to evaluate how individual studies affected meta-analysis results [24].In order to determine the influence of study characteristics on the outcome, subgroup analyses were performed according to the study design, the mean age of the patients, average MELD score at baseline, evaluating scale for frailty, followup duration, and study quality scores.Subgroups were defined based on the medians of continuous variables.A funnel plot is used to estimate publication bias based on visual symmetry judgments, along with Egger's regression asymmetry test [25].The statistical analyses were carried out with RevMan (Version 5.  Following the title and abstract screening, 861 studies were excluded as they did not align with the objectives of the meta-analysis.A comprehensive full-text review of 41 studies was then conducted, excluding 24 studies for the reasons specified in Fig 1 .Consequently, 17 studies met the criteria and were included in the subsequent meta-analysis [26][27][28][29][30][31][32][33][34][35][36][37][38][39][40][41][42].

Study characteristics
The characteristics of the included studies are summarized in Table 1.These studies were published between 2015 and 2023 and performed in the United States, China, Germany, Chile,  Slovakia, Spain, Thailand, Canada, and India.As for the study design, were prospective cohort studies [27][28][29][30][32][33][34][35][36][39][40][41][42], and four were retrospective cohort studies [26,31,37,38].A total of 6273 patients with cirrhosis were included in the meta-analysis.The sample size of the included studies varied from 116 to 1044.The mean ages of the included patients were 50.2 to 64.0 years, with the proportions of men varying from 46.2% to 96.6%.The average MELD score of the included patients was 9 to 21 at baseline.Regarding the evaluating tool for frailty, the Liver Frailty Index (LFI) was used in nine studies [27,30,[33][34][35]37,[39][40][41], whereas for the other studies, the Activities of Daily Living scale [26], the Carolina Frailty Index [28,38], the Clinical Frailty Scale [29], the Fried Frailty Index [32,36,42], and the Hospital Frailty Risk Score [31] were used respectively.Accordingly, 1983 (31.6%) of the included patients had frailty at baseline.The follow-up durations of the included studies were 3 to 29 months (mean: 11.5 months).Multivariate regression analyses were applied in all included studies when the associations between frailty and TFS of patients with cirrhosis were estimated.Factors including age, sex, and scores for hepatic dysfunction, such as the MELD and Child-Pugh scores, were adjusted.All included studies had quality scores between seven and nine stars, indicating good quality (Table 2).

Publication bias
The funnel plots for the meta-analysis of the association between frailty and TFS in patients with cirrhosis are shown in Fig 6 .Based on visual examination, the plots are symmetrical,

Discussion
In this systematic review and meta-analysis, we combined the findings from 17 pertinent cohort studies, uncovering that cirrhotic patients with frailty exhibited notably poorer TFS than their non-frail counterparts over a follow-up period spanning 3 to 29 months.The consistent results fortify the credibility of this conclusion yielded through rigorous sensitivity analyses and well-considered subgroup analyses.These latter analyses considered study design, mean patient age, average MELD score at baseline, the scale used for evaluating frailty, followup duration, and study quality scores.The evidence amassed strongly indicates that frailty may serve as a significant predictor of TFS in patients with liver cirrhosis.The mechanisms underlying the association between frailty and a poor TFS of patients with cirrhosis may be multifactorial.A previous study including 587 patients with cirrhosis listed for liver transplantation showed that patients with frailty had significantly increased days of hospitalization and a higher incidence of infection [43], which was independent of the severity of cirrhosis as evaluated by the MELD score.Similarly, another study showed that frailty measured by gait speed was a strong risk factor for hospitalization for all cirrhosis complications, which also explained the association between frailty and poor prognosis of patients with cirrhosis [44].In addition, a recent study showed that frailty might be a risk factor for in-hospital mortality of patients with cirrhosis undergoing transjugular intrahepatic portosystemic shunt [45].These findings also suggested that cirrhotic patients with frailty may be at high risk for receiving invasive treatments, which may be another potential reason for the poor long-term clinical outcomes of these patients [45].Pathophysiologically, frailty has been related to upregulated inflammatory response, impaired systemic immune dysfunction, and gut microbiota disorder [46][47][48], which may also partly explain the association between frailty and poor TFS in patients with cirrhosis.Studies are warranted to determine the molecular pathways involved.
Results of the subgroup analyses generally suggested a consistent relationship between frailty and poor TFS of patients with cirrhosis in multiple predefined clinical conditions.As for the subgroup interaction, we found that the association between frailty and poor TFS may be more remarkable in prospective studies and studies with a high NOS.These results further validated the reliability of the results, primarily driven by high-quality studies.In addition, we found a trend toward a stronger association between frailty and poor TFS in older patients (p for subgroup difference = 0.06) and a more remarkable association in studies with follow-up over 12 months.These findings suggested that using frailty as a predictor of poor TFS may be more suitable for evaluating the long-term prognosis of older patients with cirrhosis.Although no between-subgroup difference was observed according to the different evaluating scales for frailty, LFI was mostly used among the included studies.The parameter in question was initially proposed by Lai et al. in 2017 and determined by evaluating three performance metrics: handgrip strength, chair stands, and balance [49].It is worth noting that the reproducibility of LFI has been confirmed by various researchers, thus endorsing its utilization as a reliable indicator of frailty in cirrhosis patients [50].In addition to its potential prognostic value in patients with cirrhosis, there is evidence to suggest that improvement of frailty in these patients may be associated with survival benefits [5,30].However, these findings should be validated in largescale clinical trials.The methodological strengths of this study encompass an exhaustive database search to procure the most recent literature, the inclusion of cohort studies to establish a longitudinal relationship between frailty and poor TFS, the amalgamation of data from multivariate analyses to mitigate the effects of confounding factors, and the application of multiple sensitivity and subgroup analyses to underscore the robustness of the findings.Nevertheless, the metaanalysis is not without limitations.Firstly, the approaches to evaluating frailty diverged among the studies included.Though the LFI was predominantly utilized, the optimal scale and threshold for appraising frailty in cirrhosis patients still warrant determination.Secondly, as a synthesis of observational studies, it is conceivable that unadjusted residual factors might still confound the association between frailty and poor TFS of cirrhosis patients.Moreover, the follow-up durations of the included studies were relatively short (average: 11.5 months).The potential efficacy of frailty for the prediction of long-term mortality in patients with cirrhosis should be validated in large-scale prospective studies in the future.Additionally, the impact of varying cirrhosis etiologies on the relationship between frailty and poor TFS remains unexplored.Besides, we only investigated the relationship between frailty and TFS in patients with cirrhosis.Studies are needed to determine the association between frailty and the risk of other complications in patients with cirrhosis, such as the incidence of hepatic encephalopathy.Finally, a causal link between frailty and adverse clinical outcomes in cirrhosis cannot be inferred from this meta-analysis, as it only included observational studies and only observed the outcome of liver transplant-free mortality.Clinical trials would be instrumental in assessing whether ameliorating frailty could translate into survival benefits for these patients.

Conclusion
In conclusion, the findings of this systematic review and meta-analysis suggest that frailty may serve as a significant predictor of liver transplant-free mortality in patients with cirrhosis.These insights underscore the importance of integrating frailty assessment into the clinical care protocols for cirrhosis patients.Ongoing research and concerted efforts are essential to formulate the optimal scale for evaluating frailty in this patient population and explore whether interventions to improve frailty could be associated with a reduced risk of liver transplant-free mortality.

Fig 1
Fig 1 illustrates the methodical process of literature search and study selection.Initially, 1183 records were retrieved from the database search, and 281 duplicates were subsequently

Fig 3 .
Fig 3. Forest plots for the subgroup analyses regarding the association between frailty and TFS of patients with liver cirrhosis; A, subgroup analysis according to study design; and B, subgroup analysis according to the mean age of the patients.https://doi.org/10.1371/journal.pone.0302836.g003

Fig 4 .
Fig 4. Forest plots for the subgroup analyses regarding the association between frailty and TFS of patients with liver cirrhosis; A, subgroup analysis according to average MELD score at baseline; and B, subgroup analysis according to the scales for frailty evaluation.https://doi.org/10.1371/journal.pone.0302836.g004

Fig 5 .
Fig 5. Forest plots for the subgroup analyses regarding the association between frailty and TFS of patients with liver cirrhosis; A, subgroup analysis according to follow-up durations; and B, subgroup analysis according to study quality scores.https://doi.org/10.1371/journal.pone.0302836.g005

Fig 6 .
Fig 6.Funnel plots for the publication bias underlying the meta-analysis regarding the association between frailty and TFS of patients with liver cirrhosis.https://doi.org/10.1371/journal.pone.0302836.g006